Project Summary The incidence of opioid use disorders (OUDs) has increased to near-epidemic proportions. Clinical researchers have a clear responsibility to improve access to long-term treatment in order to avoid the pattern of relapse, recurrent detoxification admissions, or overdose characteristic of present treatment efforts. While agonist maintenance with methadone or buprenorphine represents an effective long-term treatment strategy, it may be unacceptable to many individuals; this may compromise treatment seeking or prevent the initiation of maintenance treatment following detoxification. Long-acting injectable naltrexone (XR-NTX) robustly blocks the effects of opioids for at least 4 weeks and is now indicated for relapse prevention following detoxification. XR-NTX therefore represents an effective alternative to agonist treatment, but it is significantly underutilized due to hurdles associated with rapidly and tolerably transitioning active users. Indeed, about half of individuals fail to initiate XR-NTX in existing naltrexone titration protocols. Our data suggest that the N-methyl-D-aspartate receptor antagonist ketamine may be feasibly integrated into a 3-day rapid non-opioid based naltrexone titration, with sub-anesthetic infusions exerting apparent effects on spontaneous and precipitated withdrawal as well as on retention. In the proposed investigation, we aim to evaluate whether two 90-minute sub-anesthetic ketamine infusions (1.41 mg/kg), compared to 2 infusions of the control midazolam (0.04 mg/kg), improve outcomes in opioid dependent individuals engaged in a rapid non-opioid based oral naltrexone titration, followed by XR-NTX maintenance. The primary outcome will be the proportion of participants to initiate XR-NTX. Secondary outcomes include abstinence rates, 3-month retention, and withdrawal severity. The investigators' extensive experience with sub-anesthetic ketamine infusions and with antagonist-based treatment of opioid dependence supports the feasibility of this novel protocol. If successful, this trial would represent a major advance in efforts to identify novel pharmacotherapies for OUD management, and for addressing a critical hurdle in XR-NTX utilization. Thus it may pave the way for research into analogous compounds, such as ketamine- like antidepressants currently in development. This may ultimately serve to broaden access to effective maintenance treatment options for active users, and to reposition detoxification as a stepping-stone to long-term treatment. These data may therefore advance treatment efforts for OUDs and increase access to a larger repertoire of first-line treatments.